Conserved Mosquito/Parasite Interactions Affect Development of Plasmodium falciparum in Africa

Abstract

In much of sub-Saharan Africa, the mosquito Anopheles gambiae is the main vector of the major human malaria parasite, Plasmodium falciparum. Convenient laboratory studies have identified mosquito genes that affect positively or negatively the developmental cycle of the model rodent parasite, P. berghei. Here, we use transcription profiling and reverse genetics to explore whether five disparate mosquito gene regulators of P. berghei development are also pertinent to A. gambiae/P. falciparum interactions in semi-natural conditions, using field isolates of this parasite and geographically related mosquitoes. We detected broadly similar albeit not identical transcriptional responses of these genes to the two parasite species. Gene silencing established that two genes affect similarly both parasites: infections are hindered by the intracellular local activator of actin cytoskeleton dynamics, WASP, but promoted by the hemolymph lipid transporter, ApoII/I. Since P. berghei is not a natural parasite of A. gambiae, these data suggest that the effects of these genes have not been drastically altered by constant interaction and co-evolution of A. gambiae and P. falciparum; this conclusion allowed us to investigate further the mode of action of these two genes in the laboratory model system using a suite of genetic tools and infection assays. We showed that both genes act at the level of midgut invasion during the parasite's developmental transition from ookinete to oocyst. ApoII/I also affects the early stages of oocyst development. These are the first mosquito genes whose significant effects on P. falciparum field isolates have been established by direct experimentation. Importantly, they validate for semi-field human malaria transmission the concept of parasite antagonists and agonists.

Infection Intensity-Dependent Responses of Anopheles gambiae to the African Malaria Parasite Plasmodium falciparum

“…No additional genetic selection for malaria parasite infection was ever carried out. The strain retains a high degree of genetic diversity compared to that of other inbred laboratory colonies and remains a reasonable approximation of local field mosquitoes (20).…”

“…To eliminate transmissionblocking factors, infected blood serum was replaced by nonimmune serum: human AB serum for P. falciparum infections and serum from noninfected BALB/c mice for P. berghei infections. Infections were performed as described previously (20). To determine infection levels, mosquito guts were dissected 8 to 10 days after blood feeding and were stained with 2% Mercurochrome before microscopic examination.…”

“…Recent studies have identified mosquito genes that affect P. falciparum and the rodent malaria parasite, Plasmodium berghei, which is often used as a laboratory model, similarly; however, such conserved responses can only partly explain the vector-parasite interactions in natural settings (6,8,11,20,21). In fact, A. gambiae is not a natural vector of P. berghei, and the intensities of P. berghei infection are much higher than those commonly observed in nature with P. falciparum (2).…”

“…This appears to be due largely to robust mosquito responses that effectively reduce the number of parasites able to invade the midgut and establish infections in the hemolymph (8,22,30). Therefore, detailed understanding of the vector-parasite interactions could lead to novel strategies that can supplement current control methods.Recent studies have identified mosquito genes that affect P. falciparum and the rodent malaria parasite, Plasmodium berghei, which is often used as a laboratory model, similarly; however, such conserved responses can only partly explain the vector-parasite interactions in natural settings (6,8,11,20,21). In fact, A. gambiae is not a natural vector of P. berghei, and the intensities of P. berghei infection are much higher than those commonly observed in nature with P. falciparum (2).…”

Gene Expression Studies in Mosquitoes

“…Ablation of TEP1 transcription products prevents a type of mosquito parasite refractoriness based on melanotic encapsulation of the pathogens. Another study showed that two mosquito genes had complementary effects, with WASP having a negative and ApoII/I a positive role in parasite development (Mendes et al, 2008). Resistance to malaria parasite infection in a nonvector species An.…”